Gastric and colorectal cancers account for more than 600,000 deaths in the world each year. Gastric cancer is the fourth most prevalent cancer in the world and the second most common cause of cancer-related deaths (Torpy et al., 2010), while colon cancer is the second most common cancer in men and the third most common cancer in women (Jemal et aL, 2010). Chronic inflammation is one of the major risk factors associated with the development of both of these gastrointestinal cancers. There is a known link between gastric cancer and Helicobacter pylori infection, which is known to induce inflammatory cytokines in the stomach. Also, patients with chronic inflammatory bowel disease have an increased incidence of colon cancer that is approximately 18-19-fold compared to the general population (Gillen et al., 1994). Although a link between chronic inflammation and carcinogenesis is well established, the underlying mechanisms remain incompletely understood. Inflammatory mediators are thought to play a role in carcinogenesis by altering cell proliferation and inducing mutations that lead to the resistance of cancer cells to apoptosis. A greater understanding of the underlying mechanisms linking inflammation and gastrointestinal (GI) cancers is likely to lead to improved therapeutics.
MAP kinase-activated protein kinase 2 (MK2) is a downstream enzyme of the p38 pathway that is involved in multiple cellular processes such as inflammatory responses, gene expression regulation and cell proliferation. Furthermore, activation of MK2 leads to downstream activation of Heat Shock Protein 27 (HSP27), a protein known to inhibit apoptosis, as well as regulate cell development and differentiation. Based on these facts and that MK2 is upregulated in gastric and colon cancers, we hypothesize that MK2 small molecule inhibitors, will be a potential therapeutic modality for gastrointestinal tumors. We have recently demonstrated that mice lacking MK2 (MK2 knockout mice) do not develop gastric or colon tumors in established models of both tumor types. The significant results we have obtained could not have been predicted by the existing literature, and the hypothesis that MK2 inhibition will be an effective treatment in patients with gastrointestinal tumors is a new concept for which the present application has been filed.